PRODUCT MONOGRAPH PrFLAGYL® (Metronidazole) 10% w/w Cream Antibacterial - Antiprotozoal sanofi-aventis Canada Inc. Date of Revision: 2905 Place Louis R.-Renaud August 7, 2018 Laval, Quebec H7V 0A3 Submission Control No. 217063 s-a Version 10.0 dated August 7, 2018 Page 1 of 31 PRODUCT MONOGRAPH PrFLAGYL® (metronidazole) 10% w/w Cream THERAPEUTIC CLASSIFICATION Antibacterial - Antiprotozoal ACTION AND CLINICAL PHARMACOLOGY Metronidazole is bactericidal against anaerobic bacteria; it exerts trichomonacidal activity and is also active against Giardia lamblia and Entamoeba histolytica. Its exact mechanism of action has not been entirely determined as yet. It has been proposed that an intermediate in the reduction of metronidazole, produced only in anaerobic bacteria and protozoa is bound to deoxyribonucleic acid and electron-transport proteins, inhibits subsequent nucleic acid synthesis. INDICATIONS AND CLINICAL USES PROTOZOAL INFECTIONS FLAGYL is indicated in the treatment of trichomonal infections in women (protozoal infection caused by Trichomonas vaginalis). BACTERIAL VAGINOSIS FLAGYL is indicated for the treatment of bacterial vaginosis (see BIBLIOGRAPHY section). FLAGYL has antibacterial and antiprotozoal properties. To reduce the development of drug- resistant bacteria/protozoans and maintain the effectiveness of FLAGYL and other antibacterial/antiprotozoal drugs, FLAGYL should be used only to treat infections that are proven or strongly suspected to be caused by bacteria/protozoans. Page 2 of 31 CONTRAINDICATIONS FLAGYL (metronidazole) is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives. FLAGYL should not be administered to patients with active neurological disorders or a history of blood dyscrasia, hypothyroidism or hypoadrenalism. WARNINGS General Metronidazole has been shown to be carcinogenic in mice and rats (see PRECAUTIONS section). Unnecessary use of the drug should be avoided. Its use should be reserved for the conditions described in the INDICATIONS AND CLINICAL USES section. FLAGYL (metronidazole) has no direct activity against aerobic or facultative anaerobic bacteria. In patients with mixed aerobic-anaerobic infections appropriate concomitant antibiotics active against the aerobic component should be considered. Known or previously unrecognized moniliasis may present more prominent symptoms after treatment with metronidazole. The effectiveness of condoms or diaphragms could be impaired by some of the fatty constituents contained in the metronidazole gynecological cream, therefore their use during treatment with FLAGYL vaginal cream is not recommended. Neurologic Severe neurological disturbances (i.e. convulsive seizures and peripheral neuropathy) have been reported in patients treated with metronidazole. These have been observed very infrequently. Patients should be warned about the potential for confusion, dizziness, hallucinations, convulsions or transient visual disorders, and advised not to drive or operate machinery if these symptoms occur. Metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system diseases due to the risk of neurological aggravation. Patients should be advised not to take alcohol or alcohol-containing medicines during metronidazole therapy and for at least one day afterwards because of the possibility of a disulfiram-like (Antabuse effect) reaction. Page 3 of 31 Hepatic Metronidazole should be used with great caution in patients with a history of hepatic enzyme increase or liver injury associated with previous administration of metronidazole (see ADVERSE REACTIONS section). Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome, with very rapid onset after treatment initiation, in patients with Cockayne syndrome have been reported with products containing metronidazole for systemic use. In this population, metronidazole should therefore only be used after careful benefit-risk assessment and only if no alternative treatment is available. Liver function tests must be performed just prior to the start of therapy, throughout and after end of treatment until liver function is within normal ranges, or until the baseline values are reached. If the liver function tests become markedly elevated during treatment, the drug should be discontinued. Patients with Cockayne syndrome should be advised to immediately report any symptoms of potential liver injury to their physician and stop taking FLAGYL. Skin Cases of severe bullous skin reactions such as Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or acute generalized exanthematous pustulosis (AGEP) have been reported with metronidazole (see ADVERSE REACTIONS). If symptoms or signs of SJS, TEN or AGEP are present, FLAGYL treatment must be immediately discontinued. Susceptibility/Resistance Development of Drug-Resistant Organisms Prescribing FLAGYL in the absence of a proven or strongly suspected bacterial or protozoal infection is unlikely to provide benefit to the patient and risks the development of resistant organisms. Potential for Microbial Overgrowth Prolonged use of FLAGYL may result in overgrowth of non-susceptible bacteria and protozoans. If the infection is not improved following 2 treatment courses of 10 days, cultures should be obtained to guide further treatment. If such infections occur, discontinue use and institute alternate therapy. Culture and susceptibility studies should be performed to determine the causative organisms and their susceptibility to metronidazole. Based on clinical judgment and anticipated bacteriological findings, therapy may be started while awaiting the results of these tests. However, modification of the treatment may be necessary once these results become available. Page 4 of 31 In mixed aerobic and anaerobic infections, consideration should be given to the concomitant administration of an antibiotic appropriate for the treatment of the aerobic component of the infection (see WARNINGS section). Metronidazole has also been used in the treatment of a small number of cases of brain or lung infections (some with abscesses) caused by anaerobic bacteria. PRECAUTIONS General Where there is clinical evidence of a trichomonal infection in the sexual partner, he should be treated concomitantly to avoid reinfection. A rare case of reversible but profound neurological deterioration has been reported following a single oral dose of metronidazole; it is therefore advisable that a patient taking metronidazole for the first time not be left unattended for a period of two hours. The appearance of abnormal neurologic signs demands prompt discontinuation of metronidazole therapy and, when severe, immediate medical attention. Activated charcoal may be administered to aid in the removal of unabsorbed drug, if no more than two or three hours have elapsed since administration of the drug. If for compelling reasons, metronidazole must be administered longer than the usually recommended duration, it is recommended that patients should be monitored for adverse reactions such as peripheral or central neuropathy (such as paresthesia, ataxia, dizziness, convulsive seizures). Treatment with FLAGYL should be discontinued if ataxia or any other symptom of central nervous system (CNS) involvement occurs. Patients with severe hepatic disease (including hepatic encephalopathy) metabolize metronidazole slowly with resultant accumulation of metronidazole and its metabolites in the plasma. Treatment with FLAGYL should be discontinued should pancreatitis occur once other causes of this disease are excluded. Administration of solutions containing sodium ions may result in sodium retention. Care should be taken when administering metronidazole injection to patients receiving corticosteroids or to those predisposed to edema. Patients should be warned that FLAGYL may darken urine. This is probably due to a metabolite of metronidazole and seems to have no clinical significance (see ADVERSE REACTIONS section). Page 5 of 31 Hematologic Transient eosinophilia and leukopenia have been observed during treatment with FLAGYL. Hematological tests, especially regular total and differential leukocyte counts are advised if administration for more than 10 days or a second course of therapy is considered to be necessary. Carcinogenesis, Mutagenesis, Impairment of Fertility Metronidazole has been shown to be carcinogenic in the mouse and in the rat. However similar studies in the hamster have given negative results. Metronidazole has been shown to be mutagenic in bacteria in vitro. In studies conducted in mammalian cells in vitro as well as in rodent in vivo, there was inadequate evidence of mutagenic effect of metronidazole. Prominent among the effects in the mouse was the promotion of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At very high dose levels (approximately 1500 mg/m2 which is approximately 3 times the most frequently recommended human dose for a 50 kg adult based on mg/m2), there was a statistically significant increase in the incidence of malignant liver tumors in males. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically